COMPOSITIONS, BIOMARKERS AND THEIR USE IN THE TREATMENT OF CANCER
The present invention relates to compositions, biomarkers, and their use in treatment of cancer. In some embodiments, the invention relates to the use of several biomarkers in methods for determining the responsiveness of a human subject to a specific compound, methods for monitoring the efficacy of the compound, or methods for treating a human subject.
1 . A method for determining the responsiveness of a human subject comprising determining the level of activity of KLF4 in a biological sample from a human subject, wherein a lower than normal level of KLF4 activity is indicative that the human subject is responsive to the compound of formula I:
2 . The method of claim 1 , wherein a lower than normal level of KLF4 activity is indicative that the human subject is responsive to the compound of formula I for treatment of acute myelogenous leukemia (AML).
3 . The method of claim 1 , wherein a lower than normal level of KLF4 activity is indicative that the human subject is responsive to the compound of formula I for treatment of myelodysplastic syndrome (MDS), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), adult T-cell leukaemia (ATLL), lymphoma, gastric cancer, or multiple myeloma.
4 . The method of claim 1 , wherein the human subject has AML.
5 . The method of claim 1 , wherein the human subject has MDS, ALL, CML, ATLL, lymphoma, gastric cancer, or multiple myeloma.
6 . A method for monitoring the efficacy of the compound of formula I comprising determining the level of activity of KLF4 in a human subject under treatment with the compound of formula I:
wherein an increase of the level of activity of KLF4 directly related to the treatment with the compound of formula I indicates the efficacy of the compound of formula I and wherein a decrease or unchanged level of activity of KLF4 during the treatment with the compound of formula I indicates the lack of efficacy of the compound of formula I.
7 . The method of claim 6 , wherein the human subject is treated for AML.
8 . The method of claim 6 , wherein the human subject is treated for MDS, ALL, CML, ATLL, lymphoma, gastric cancer, or multiple myeloma.
9 . A method for treating a human subject comprising determining the level of activity of KLF4 in a human subject and administering to the human subject an effective amount of a compound or a pharmacologically acceptable salt or solvate thereof, the compound having formula I:
if the level of KLF4 activity of the human subject is lower than normal.
10 . The method of claim 9 , wherein the human subject has AML.
11 . The method of claim 9 , wherein the human subject has MDS, ALL, CML, ATLL, lymphoma, gastric cancer, or multiple myeloma.
12 . A method for determining the responsiveness of a human subject comprising assaying for a genetic alteration of CDX2 or determining the level of activity of CDX2 in a biological sample from a human subject, wherein the presence of a genetic alteration of CDX2 or an abnormal level of CDX2 activity is indicative that the human subject is responsive to the compound of formula I:
13 . The method of claim 12 , wherein the presence of a genetic alteration of CDX2 or an abnormal level of CDX2 activity is indicative that the human subject is responsive to the compound of formula I for treatment of AML.
14 . The method of claim 12 , wherein the presence of a genetic alteration of CDX2 or an abnormal level of CDX2 activity is indicative that the human subject is responsive to the compound of formula I for treatment of MDS, ALL, CML, ATLL, lymphoma, gastric cancer, colorectal cancer or multiple myeloma.
15 . The method of claim 12 , wherein the human subject has AML.
16 . The method of claim 1 , wherein the human subject has MDS, ALL, CML, ATLL, lymphoma, gastric cancer, colorectal cancer or multiple myeloma.
17 . A method for treating a human subject comprising assaying for a genetic alteration of CDX2 or determining the level of activity of CDX2 in a biological sample from a human subject and administering to the human subject an effective amount of a compound or a pharmacologically acceptable salt or solvate thereof, the compound having formula I:
if the level of activity of CDX2 of the human subject is higher than normal or in the presence of a genetic alteration of CDX2 in the human subject.
18 . The method of claim 17 , wherein the human subject has AML.
19 . The method of claim 17 , wherein the human subject has MDS, ALL, CML, ATLL, lymphoma, gastric cancer, colorectal cancer or multiple myeloma.
20 . The method of claim 1 , further comprising assaying for a genetic alteration of CDX2 or determining the level of activity of CDX2 in the biological sample from the human subject, wherein a lower than normal level of KLF4 activity in combination with the presence of a genetic alteration of CDX2 or a higher than normal level of CDX2 activity is indicative that the human subject is responsive to the compound of formula I.
21 . The method of claim 9 , further comprising assaying for a genetic alteration of CDX2 or determining the level of activity of CDX2 in the biological sample from the human subject, and administering to the human subject an effective amount of the compound of formula I, or the pharmacologically acceptable salt or solvate thereof, if the level of KLF4 activity of the human subject is lower than normal in combination with the presence of a genetic alteration of CDX2 or a higher than normal level of CDX2 activity.
22 . A method for determining the responsiveness of a human subject comprising determining the level of activity of at least two biomarkers in a biological sample from a human subject, wherein at least one biomarker is CDX2, and at least one other biomarker is KLF4, wherein an abnormally high ratio of CDX2/KLF4 activity and/or an abnormally low ratio of KLF4/CDX2 is indicative that the human subject is responsive to the compound of formula I:
23 . The method of claim 22 , wherein the activity is gene copy number.
24 . The method of claim 22 , wherein an abnormally high ratio of CDX2/KLF4 activity and/or an abnormally low ratio of KLF4/CDX2 is indicative that the human subject is responsive to the compound of formula I for treatment of AML.
25 . The method of claim 22 , wherein an abnormally high ratio of CDX2/KLF4 activity and/or an abnormally low ratio of KLF4/CDX2 is indicative that the human subject is responsive to the compound of formula I for treatment of MDS, ALL, CML, ATLL, lymphoma, gastric cancer, colorectal cancer or multiple myeloma.